TCR-Engineered T-Cell Dosing With Delayed PD-1 Blockade

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Solution Overview

Problem

Cancer cells modulate immune responses through an immunosuppressive tumour microenvironment, challenging the maintenance of an activated and sustained T cell response for effective tumour elimination.

Innovation Solution

Administering tumour-specific T cells engineered with a heterologous CD8 co-receptor and TCR capable of binding to MAGE-A4, combined with a PD-1 axis binding antagonist about three to five weeks after T cell administration, to sustain T cell function and enhance therapeutic effect.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If tumour-specific T cells are administered to treat cancer, then anti-tumour immune response is enhanced, but T cell function is compromised due to immunosuppressive tumour microenvironment

Engineering Contradiction:

Improveanti-tumour immune responseVSAvoidimmunosuppressive tumour microenvironment

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

A PD-1 axis binding antagonist is introduced as an intermediary substance that mediates between the T cells and the tumour microenvironment. This antagonist blocks the PD-1 pathway, preventing the tumour's immunosuppressive signals from directly inhibiting T cell function, thereby enabling T cells to maintain their anti-tumour activity despite the presence of the immunosuppressive microenvironment.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the functional parameters of the T cells by administering a PD-1 axis binding antagonist that alters the PD-1 pathway activity. This parameter change enables T cells to transition from a suppressed state to an activated state, improving their ability to recognize and destroy tumour cells while maintaining memory formation capabilities.

Inventive Principle:

Principle #35Parameter changes

2Duration of action of moving object

If T cell response is sustained to eliminate tumour, then therapeutic effect is improved, but T cell exhaustion is promoted by immunosuppressive microenvironment

Engineering Contradiction:

ImproveT cell response durationVSAvoidT cell exhaustion

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The PD-1 axis binding antagonist serves as a protective intermediary that shields T cells from exhaustion signals. By blocking the PD-1 pathway, the antagonist prevents the tumour microenvironment from inducing T cell exhaustion, thereby allowing T cells to maintain their functional capacity and persistence over extended periods.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent converts the harmful PD-1 pathway activation (which normally leads to T cell exhaustion) into a beneficial state by using the binding antagonist to block this pathway. This transforms the immunosuppressive signal into a non-inhibitory state, allowing T cells to sustain their anti-tumour response without exhaustion.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Reliability

If combination therapy with PD-1 axis binding antagonist is administered, then T cell function is sustained, but treatment complexity increases

Engineering Contradiction:

ImproveT cell functionVSAvoidcombination therapy regimen

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The PD-1 axis binding antagonist is administered at a specific time point (about three to five weeks after T cell infusion) when T cells have initially expanded but before full anti-tumour activity is achieved. This preliminary timing allows the antagonist to prime the T cell response and prevent exhaustion before the main therapeutic effect occurs, simplifying the overall treatment strategy.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The combination therapy uses periodic administration of the PD-1 axis binding antagonist at specific intervals (about three to five weeks after T cell administration). This periodic dosing schedule maintains T cell function while avoiding continuous exposure that would increase complexity, allowing the system to cycle through activation and rest phases.

Inventive Principle:

Principle #19Periodic action

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The combination therapy enhances and prolongs the anti-tumour immune response by maintaining T cell activity and transitioning to memory T cells, overcoming immunosuppression in the tumour microenvironment.

Implementation Method 1

administering an initial dose of a PD-1 axis binding antagonist to the individual about three weeks to about five weeks after step (a)

Methodology Applied

Scientific EffectPD-1 axis binding:

Implementation Method 2

modified T cells comprising a heterologous CD8 co-receptor and a heterologous TCR capable of binding to MAGE-A4

Methodology Applied

Scientific EffectTCR binding:

Implementation Method 3

modified T cells comprising a heterologous CD8 co-receptor and a heterologous TCR capable of binding to MAGE-A4

Methodology Applied

Scientific EffectCo-receptor interaction:

Data Source

PatentUS20250367289A1Dosage regimen for a combination therapy consisting oftcr-engineered t-cells in combination with a PD-1 axis binding antagonist

Publication Date: 2025.12.04 USWM CT LLC

AI summary

The disclosure relates to a method of treating cancer, and to a population of modified T cells for use in a method of treating cancer.